Anaplastic thyroid cancer (ATC) is an aggressive malignancy with limited options for treatment. Targeting epigenetic modifications via interfering with the interaction between the bromodomain and extra-terminal domain (BET) proteins and acetylated histones by using BET inhibitors (e.g., JQ1) has shown some efficacy in thyroid cancer. To improve the efficacy, an inhibitor of MEK, trametinib, was tested together with JQ1as a combined treatment via cell-based approaches and xenograft studies. We examined the effects of combined treatment of JQ1 and trametinib on the proliferation of human ATC cell lines (THJ-11T and THJ-16) in vitro. We further evaluated the effects of the combined treatment on tumor development in vivo using mouse xenograft models. We elucidated the underlying molecular pathways affected by double treatment. We showed that the combined treatment totally blocked proliferation, while either JQ1 or trametinib alone only had partial effects. Combined treatment suppressed MYC expression more than single treatment, resulting in decreased expression of pro-survival regulators and increased pro-apoptotic regulators to collaboratively induce apoptosis. In xenograft studies, single treatment only partially inhibited tumor growth, but the combined treatment inhibited tumor growth by 90%. The reduction of tumor growth was mediated by synergistic suppression of MYC, to affect apoptotic regulators to markedly promote tumor apoptosis. Combined treatment of BET and MEK-ERK inhibitors was more effective to treat ATC than single targeted treatment. Synergistic suppression of MYC transcription via collaborative actions on chromatin modifications suggested that targeting epigenetic modifications could provide novel treatment opportunities for ATC.